Abstract The human adaptive immune system recognizes two aspects of antigens. Structural epitopes are detected by B cells, while their sequence is detected by CD4+ and CD8+ T cells. Recent advances in genomics and the development of bioinformatics epitope processing and presentation prediction tools allow us now to quantitatively define the self and foreign immune system epitope repertoires. We have previously developed detailed libraries of the self and foreign CD8+ T cell epitope repertoires, and demonstrated that these libraries contain a vast amount of information. Some examples include a direct relation between the number of epitopes of different HLAs and their relation to autoimmune diseases, as well as a relation between the function of a viral protein or its expression stage and the number of epitopes it possesses. We now propose to use a multidisciplinary approach to improve and expand this analysis to the other two arms of the adaptive immune system and define detailed libraries of B cell epitopes and CD4+ T cell epitopes for the most frequent MHC class II alleles, as well as epitopes presented to C8+ T cell by non-classical MHC molecules. We then propose to analyze the repertoire properties emerging from these libraries down to the single protein level. The proposed work necessitates a combination of genomics, immunology, virology and bioinformatics and will be conducted in close collaboration with experimentalists. The proposed research plan will lead, beyond the immunological understanding, to new and better epitope prediction tools for the use of the scientific community. The developed epitope libraries will be used for both practical and basic science issues. At the basic science level, we plan for example, to use these libraries to study the origins of autoimmunity and its linkage to the host MHC haplotype, understand the interplay between the different arms of the immune system and check the role of pathogen epitope mimicry in autoimmunity. At the practical level, the proposed research has wide applications in multiple domains, such as: the detection of optimal targets for cancer immunotherapy, the development of immune boosting treatment following transplantation or for immuno-deficient patients, and the development of T cell vaccination strategies. Another possible application is the detection of MHC haplotypes with overlapping epitopes for optimal match in allogeneic transplantations.